Project Summary: Drug resistant epilepsy (DRE) remains a difficult biomedical challenge, affecting approximately one-third of newly-treated cases of epilepsy. Individuals impacted by DRE endure a poor quality of life, and can face life-threatening complications. Surgical removal of epileptogenic tissue can dramatically reduce seizures and improve quality of life. However, epilepsy surgery can be highly invasive, may produce damage that is not restricted to the target tissue, and is not feasible in certain critical areas of the brain. Also, surgical damage that is not conformal to its target and affects neighboring, eloquent tissue can produce long- term functional deficits. Finally, incomplete resection or ablation of target tissue can result in poor seizure management. The purpose of this proposal is to develop and test a non-invasive, targeted, conformal surgical strategy that will optimize seizure control, expand the types of epilepsies amenable to surgical intervention, and, ultimately, improve the quality of life of patients with DRE. This project will utilize Magnetic Resonance- guided, low-intensity Focused Ultrasound (MRg-FUS) to focally and reversibly open the blood brain barrier (BBB) in a targeted manner without producing a thermal lesion. Transient opening of the BBB allows timed delivery of an otherwise BBB-impermeable neurotoxin to the brain parenchyma in order to produce a focal, axon-sparing lesion of targeted neurons. The neurotoxin Quinolinic Acid (QA) is well tolerated when administered systemically at high dosages, exhibits little or no permeability through the intact BBB, is relatively unaffected by glutamatergic uptake systems in the brain parenchyma, and is capable of producing axon- sparing lesions. We present here the first evidence that systemically-administered QA combined with MRgFUS produces focal neuronal damage, while sparing axons in precisely targeted regions of the brain. Moreover, this approach affords the opportunity to treat targets that would be difficult, if not impossible, to treat using currently-available surgical techniques. Finally, these outcomes can be achieved while simultaneously limiting the risks of collateral damage, surgical side effects, and long-term neurological deficits. The current project will develop and test this novel approach for limiting seizures using a model of limbic epilepsy. The guiding hypothesis is that targeted disconnection of dysfunctional brain circuitry can be achieved in a precise, conformal, and non-invasive manner, and that this strategy can be implemented to control seizures and improve neurological outcomes. This approach provides distinct advantages over current surgical modalities as it will restrict the extent of tissue damage, allow treatment of regions that are otherwise inaccessible, reduce peri-surgical complications, mitigate against long-term functional deficits, and do all of this in a non-invasive manner. Notably, this strategy could prove useful for treating a variety of neurological disorders in which disturbances in connectivity play a role.